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DHA supplementation suppresses LDLR and OLR1 gene expression in blood cells from hypertriglyceridemic men

ABSTRACT: Previously published results from our double-blind, placebo-controlled parallel study with docosahexaenoic acid (DHA) supplementation (3 g/d, 90 d) to hypertriglyceridemic men (39-66yr) showed that DHA reduced several risk factors for cardiovascular disease (CVD), including the plasma concentration of inflammatory markers. To determine the effect of DHA supplementation on the global gene expression pattern, we performed Affymetrix GeneChip microarray analysis of blood cells (treated with lipopolysaccharide (LPS) or vehicle) drawn before and after the supplementation from the hyperlipidemic men who participated in the previous study. Genes that were significantly differentially regulated by the LPS treatment and DHA supplementation were identified. Differential regulation of 18 genes was then confirmed by quantitative RT-PCR. Both microarray and qRT-PCR data showed that the expression of LDL receptor (LDLR), oxidized LDL receptor (OLR1), and cathepsin L1 (CTSL) was significantly suppressed by DHA supplementation; however, LPS stimulated the expression of LDLR and CTSL but not that of OLR1. LPS up-regulated and DHA suppressed the expression of prostaglandin E synthase (PTGES), PPAR delta, and various chemokines. Enrichment with Gene Ontology categories demonstrated that the genes related to transcription factor activity, immune responses, host defense responses, inflammatory responses, and apoptosis were inversely regulated by LPS and DHA. These results provide supporting evidence for the anti-inflammatory effects of DHA supplementation, and reveal previously unrecognized genes that are regulated by DHA, and are associated with risk factors of cardiovascular diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE20114 | GEO | 2010/01/30

SECONDARY ACCESSION(S): PRJNA124247

REPOSITORIES: GEO

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Project description:Preclinical and clinical studies suggest that consumption of long chain omega-3 polyunsaturated fatty acids (PUFAs) reduces severity chronic and autoimmune diseases. These ameliorative effects have been conventionally linked in part to downregulation of expression of proinflammatory cytokine and chemokine genes and more recently, associated with inhibition of Type 1 interferon (IFN1)-regulated gene expression. Here we used single cell RNA sequencing (scRNAseq) to gain new mechanistic perspectives of how the omega-3 PUFA docosahexaenoic acid (DHA) influences TLR4-driven proinflammatory and IFN1-regulated gene expression in a novel self-renewing murine fetal liver-derived macrophage (FLM) model. FLMs were cultured with 25 µM DHA or vehicle for 24 h, treated with modest concentration of LPS (20 ng/ml) for 1 and 4 h, and then subjected to scRNAseq using 10X Chromium System. At 0 h (i.e., in the absence of LPS), DHA increased expression of genes associated with the NRF2 antioxidant response (Sqstm1, Hmox1, Chchd10) and metal homeostasis (Mt1, Mt2, Ftl1, Fth1) suggesting cells are polarized towards a more anti-inflammatory phenotype. At 1 h post-treatment, DHA inhibited LPS-induced cholesterol synthesis genes (Scd1, Scd2, Pmvk, Cyp51, Hmgcs1, and Fdps) which potentially could contribute to interference with TLR4-mediated inflammatory signaling. At 4 h post-treatment, LPS-treated FLMs reflected a robust proinflammatory response including upregulation of cytokine (Il1a, Il1b, Tnf) and chemokine (Ccl2, Ccl3, Ccl4, Ccl7) genes as well as IFN1-regulated (Irf7, Mx1, Oasl1, Ifit1) genes, many of which were suppressed by DHA. Using SCENIC analysis to identify gene expression networks, we found DHA modestly downregulated LPS-induced expression of NF-κB-target genes. Moreover, LPS induced a subset of FLMs simultaneously expressing NF-κB- and IRF7/STAT1/STAT2-target genes that were conspicuously absent in DHA-pretreated FLMs, suggesting that DHA more potently targets the IFN1 response over the NF-kB response. Altogether, scRNAseq generated a valuable dataset that provides new insights into multiple overlapping mechanisms by which DHA may transcriptionally or post-transcriptionally regulate LPS-induced proinflammatory and IFN1-driven responses in macrophages

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DHA supplementation suppresses LDLR and OLR1 gene expression in blood cells from hypertriglyceridemic men

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